Abstract
Traditional Chinese Medicines are promising sources of new agents for controlling cancer metastasis. Compound Kushen Injection (CKI), prepared from medicinal plants Sophora flavescens and Heterosmilax chinensis, disrupts cell cycle and induces apoptosis in breast cancer; however, effects on migration and invasion remained unknown. CKI, fractionated mixtures, and isolated components were tested in migration assays with colon (HT-29, SW-480, DLD-1), brain (U87-MG, U251-MG), and breast (MDA-MB-231) cancer cell lines. Human embryonic kidney (HEK-293) and human foreskin fibroblast (HFF) served as non-cancerous controls. Wound closure, transwell invasion, and live cell imaging showed CKI reduced motility in all eight lines. Fractionation and reconstitution of CKI demonstrated combinations of compounds were required for activity. Live cell imaging confirmed CKI strongly reduced migration of HT-29 and MDA-MB-231 cells, moderately slowed brain cancer cells, and had a small effect on HEK-293. CKI uniformly blocked invasiveness through extracellular matrix. Apoptosis was increased by CKI in breast cancer but not in non-cancerous lines. Cell viability was unaffected by CKI in all cell lines. Transcriptomic analyses of MDA-MB-231indicated down-regulation of actin cytoskeletal and focal adhesion genes with CKI treatment, consistent with observed impairment of cell migration. The pharmacological complexity of CKI is important for effective blockade of cancer migration and invasion.
Highlights
Cancer progression results from uncontrolled migration of cells away from the primary tumor, intravasation into lymphatic or vascular circulation, invasion into secondary tissues and the formation of metastasized tumors [1, 2] which are the main cause of cancer-related deaths [3,4,5]
Enriched Gene Ontology (GO) terms connected to cell migration such as “positive regulation of locomotion,” “tissue migration,” and “leucocyte migration” emerged from analyses of differentially expressed (DE) genes in Compound Kushen Injection (CKI)-treated MDA-MB-231 cells (Supplementary Image 1 and Supplementary Data Sheet 1)
Integration of DE genes associated with CKI treatment into Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways showed that some of the most over-represented pathways were “focal adhesion,” “regulation of actin cytoskeleton,” “pathways in cancer,” “TGF-β signaling pathway,” and “adherens junction” (Figure 1)
Summary
Cancer progression results from uncontrolled migration of cells away from the primary tumor, intravasation into lymphatic or vascular circulation, invasion into secondary tissues and the formation of metastasized tumors [1, 2] which are the main cause of cancer-related deaths [3,4,5]. New approaches for enhancing cancer treatment by impairing cell migration and metastasis might offer promise for curing patients with malignancies. Combinations of anticancer therapeutic regimens that reduce cell proliferation and limit metastasis would be advantageous [7,8,9]. Traditional Chinese medicine (TCM) relies on natural product extracts containing complex mixtures of components, suggested to deliver therapeutic benefit to individuals suffering from non-small cell lung cancer, liver, breast, and colorectal cancers [10, 13, 14]. The inherent complexity of TCM suggests principle components might act in concert with adjuvant components, explaining an apparent synergy in therapeutic benefits seen from the whole extract as compared to individual compounds [15]. Modulation of multiple regulatory signaling targets has been proposed as essential for the anti-proliferative, anti-migratory and anti-metastatic properties of TCMs [16, 17]
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